Significance Simian Immunodeficiency Virus (SIV) infection of macaques is considered the best animal model for AIDS. Despite intense effort, no protective vaccine against SIV has been found. Objectives This study will test whether nucleic acid vaccination can produce protective immunity against SIV infection. We will use the optimal vaccination conditions that we determined in the first part of this study to vaccinate animals and closely follow the induced immune response. Results Four groups of four animals are used in this study. Each group has a slightly different experimental protocol. Animals are vaccinated twice, at the start of the experiment and at 3 months. We are performing several different measurements of the induced humoral and cellular immunity. Eight months after the first injection, animals will be challenged orally with SIV and followed for another 6 months. Animals will be monitored for both resistance to viral infection and resistance to the development of disease. Future Directions If we are able to produce protective immunity, the next experimental question will be what component of host immunity was able to produce the protection. A second direction will be applying the result ot produce a human HIV vaccine. KEYWORDS SIV, vaccine